The normal cornea has no blood or lymphatic vessels. This feature is essential for corneal transparency and optimal visual performance, and contributes to the immunologic privilege of the cornea.
Neovascularization (NV) is a common complication secondary to various corneal diseases, including infection, degeneration, trauma and stem cell deficiency-induced insults. NV is also strongly associated with graft failure after corneal transplantation. Additionally, corneal NV as a result of viral or chlamydial (trachoma) infection is a leading cause of visual impairment worldwide.
Corneal NV is a complex response to a number of stimuli, and involves a sequence of coordinated cellular and molecular mechanisms. Dilation of the existing limbal vessels followed by adhesion and diapedesis of leukocytes, such as neutrophils and macrophages, and migration and proliferation of vascular endothelial cells (EC), in large part mediated by VEGF, are all important factors in NV pathogenesis (1,2,3).
Limited therapeutics are available to topically treat inflammation in the cornea that are also able to regulate unwanted neovascularization of the corneal tissue. Current anti-inflammatories for topical treatments in the eye, i.e., applied directly to the cornea, include steroids, which are well appreciated by the clinical community to have long-term deleterious side effects. Such side effects include well-known complications such as cataracts, infection and glaucoma.
Angiogenesis is a fundamental process by which new capillaries are formed from existing blood vessels. This process plays important roles in physiological events such as formation of the corpus luteum, development of the embryo and wound healing, including recovery from both myocardial ischemia and peptic ulcer (1). Unregulated growth of blood vessels can contribute to tissue injury in a large number of diseases such as arthritis, diabetes, and tumor progression (2). Endothelial cells are normally quiescent and are activated during the angiogenic response. Upon stimulation, endothelial cells can degrade their basement membrane and proximal extracellular matrix, migrate directionally, then divide and organize into functional capillaries invested by a new basal lamina (3).
There is a growing body of evidence demonstrating that the angiogenic switch is regulated by the net balance between positive and negative regulators of new capillary growth (2). Persistence of neovascularization requires a pro-angiogenic environment, with the expression of angiogenic factors outweighing that of angiostatic factors. A range of peptides can influence this balance, including mitogenic factors such vascular endothelial growth factor (VEGF) (3), nonmitogenic factors (selected cytokines, CXC chemokines), and internal peptide fragments of angiostatin and endostatin (3). Certain eicosanoids also have potent biologic actions on vascular endothelial cells. In rabbits, PGE2, PGR2α, and prostacylin (PGI2) stimulate angiogenesis where prostaglandin E series, in particular PGE1, is most potent. PGE2 is a potent inducer of VEGF expression in synovial fibroblasts. In addition to its known vasodilator and antiplatelet properties, PGI2 can also induce VEGF gene expression and protein synthesis (4).
It was recently reported that 12-lipoxygenase activity and one of its products, 12(S)-HETE, is required for angiogenic responses (5), and that P450-derived 12R-HETE stimulates angiogenesis via NF-kB (6). The cyclooxygenase-2 (COX-2) gene in endothelial cells is rapidly upregulated by several growth factors as well as inducers of angiogenesis (7). Along these lines, results using three different endothelial cell models show that COX-2 is an essential component of angiogenesis, at least in vitro (8). Nonsteroidal anti-inflammatory drugs such as aspirin (ASA) have been implicated in the prevention of certain cancers such as lung and colon cancer (9, 10) that might be related to ASA's ability to reduce angiogenesis (7).
A need therefore exists, for compositions and methods to prevent angiogenesis that are directed toward the disease process, such that angiogenesis is prevented or inhibited physiologically. A need also exists for compositions and methods that induce angiogenesis in tissue that is lacking the requisite or essential physiological requirements for sustainability. Further, A need exists for an improved understanding of neovascularization as well as the isolation and preparation of bioactive agents that can serve to eliminate or diminish NV pathogenesis, especially associated with the cornea.